Method of Adjuvant Cancer Treatment

ABSTRACT

The present invention provides a method of providing adjuvant treatment to a human patient which comprises administering to such a patient therapeutically effective doses of dabrafenib and trametinib for a time period sufficient to increase relapse-free survival (RFS).

RELATED APPLICATIONS

The present disclosure is a continuation of U.S. patent application No.(USPAN) Ser. No. 17/095,200 filed Nov. 11, 2020, which is a continuationof Ser. No. 16/664,978 filed Oct. 28, 2019 and issued as U.S. Pat. No.10,869,869 on Dec. 22, 2020, which is a continuation of Ser. No.16/056,702 filed Aug. 7, 2018, which is a continuation of Ser. No.15/479,663 filed Apr. 5, 2017 which is a continuation of Ser. No.14/422,182 filed Feb. 18, 2015 which is a is a National StageApplication of PCT/US2013/057432 filed Aug. 30, 2013, which claimspriority to Ser. No. 61/696,375 filed Sep. 4, 2012 which areincorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

This invention relates to a method of treating subjects after completeresection of cutaneous melanoma.

Cutaneous melanoma is the most aggressive form of all skin cancers.Although it represents only 4% of all cancers, its incidence iscontinuing to rise in the world at a rate exceeding all other cancers(Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer JClin 2007; 57: 43-66). Worldwide it is expected that approximately132,000 people will be diagnosed with melanoma each year andapproximately 37,000 people are expected to die of the disease annually(World Health Organization (WHO). Skin cancers. In Ultraviolet radiationand the INTERSUN Programme. Retrieved 7 Feb. 2012).

Surgical resection is the treatment of choice for localized melanoma andfrequently results in cures for early stage (I and II) disease, with a90% long term (10-year) survival rate for stage I disease Balch et al.,Final Version of 2009 AJCC Melanoma Staging and Classification. J ClinOncol. 2009; 27:6199-6206). However, patients with lymph nodeinvolvement 1 mm, including those detected only by sentinel lymph nodebiopsy, are at high risk of both local and distant relapse afterdefinitive surgery due to the frequent presence of distantmicrometastatic disease at presentation (Kirkwood et al. High-doseinterferon alfa-2b significantly prolongs relapse-free and overallsurvival compared with the GM2-KLH/QS-21 vaccine in patients withresected stage II-III melanoma: Results of Intergroup TrialE1694/S9512/C509801. J Clin Oncol 2001; 19: 2370-80; Van Akkooi et al.Long-term follow-up of patients with minimal sentinel node tumor burden(<0.1 mm) according to Rotterdam criteria: A study of the EORTC MelanomaGroup. J Clin Oncol, 2009; 27:15s (suppl abstr 9005). Approximately halfof these patients will ultimately die of metastatic disease (Markovic SN, et al. Malignant melanoma in the 21st century, part 2: staging,prognosis and treatment. Mayo Clin. Proc. 2007; 82: 490-513), and themorbidity from uncontrolled relapses is also considerable. Thus there isa need for effective adjuvant therapy for high-risk patients to preventdisease relapse after surgical resection of the primary tumor.

Although significant progress has been made recently with new treatmentsfor metastatic melanoma, therapeutic options in the adjuvant settingremain limited. Many agents have been evaluated as potential therapiesfor the adjuvant treatment of melanoma however almost all havedemonstrated little or no benefit (Schuchter L. Adjuvant InterferonTherapy for Melanoma: High-Dose, Low-Dose, No Dose, Which Dose? J ClinOncol 2004; 22:7-10). The National Comprehensive Cancer Network (NCCN)treatment guidelines for melanoma recommend clinical trials, observationand interferon as the three therapy options for the adjuvant treatmentof melanoma with clinical trials as the preference (NationalComprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelinesin Oncology:Melanoma. NCCN, Ft. Washington, PA; 2012). Althoughhigh-dose interferon is currently the only approved therapy for theadjuvant treatment of melanoma it is not widely accepted as the standardof care. Increasing evidence surrounding a questionable survivalbenefit, a high incidence of serious toxicities, and negligible benefitfor patients with bulkier disease makes it an unattractive therapy formost patients and clinicians (Schuchter, 2004). Thus, there is a needfor more effective therapies with an acceptable safety profile in theadjuvant setting.

SUMMARY OF THE INVENTION

The present invention provides a method of providing adjuvant treatmentto a patient with a prior diagnosis of melanoma which has been resected,which comprises administering to such a patient therapeuticallyeffective doses of dabrafenib and trametinib for a time periodsufficient to increase relapse-free survival (RFS).

According to one embodiment of the invention, there is provided a methodof increasing relapse-free survival (RFS) after resection of melanoma,which comprises administration of a) dabrafenib and b) trametinib.

According to another embodiment of the invention, there is provided thecombination of dabrafenib and trametinib for use in increasingrelapse-free survival (RFS) after resection of melanoma.

According to another embodiment of the invention, the patient has aprior diagnosis of stage III melanoma which primary tumor has beenresected.

According to another embodiment of the invention, the patient has aprior diagnosis of BRAF V600 mutation-positive melanoma which has beenresected. According to another embodiment, the patient has stage IIIBRAF V600-mutation positive melanoma which has been resected.

DETAILED DESCRIPTION OF THE INVENTION

The RAS/RAF/MEK/ERK pathway (i.e., the MAP kinase pathway) is a criticalproliferation pathway in many human cancers, including melanoma.Oncogenic mutations in BRAF signal through MEK1 and MEK2, and occurrenceof this is an early event. This study will evaluate the combination oftwo small-molecules, oral agents, dabrafenib and trametinib. Dabrafenibis a potent and selective RAF kinase inhibitor of human wild type BRAFand CRAF enzymes as well as the mutant forms BRAFV600E, BRAFV600K andBRAFV600D. The mode of action of dabrafenib is consistent withcompetitive inhibition of adenosine triphosphate (ATP) binding. Bycontrast, trametinib is a reversible, highly selective, allostericinhibitor of MEK1 and MEK2. Trametinib is non-competitive towards ATPand inhibits both MEK activation and kinase activity. Because BRAF andMEK are in the same pathway, and because MEK is a substrate of activatedBRAF and other kinases that can be activated in presence of BRAFinhibition, inhibiting both proteins simultaneously rather thanindividually could provide more effective pathway inhibition and alsodecrease the likelihood of developing resistance.

Preliminary clinical experience, along with data generated in cell line,mouse xenograft, and rat safety models with BRAF and MEK inhibitorcombinations suggest enhanced effects on efficacy and reduced toxicitysuch as reduction of proliferative skin lesions or reduction of growthstimulation of cells containing RAS mutations compared to treatment witha BRAF inhibitor alone.

The term “dabrafenib” as used herein means the B-Raf inhibitorrepresented by the structure of formula (II):

or a pharmaceutically acceptable salt thereof.

Dabrafenib is preferably administered as its mesylate salt asN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamidemethanesulfonate.

Dabrafenib is disclosed and claimed, along with pharmaceuticallyacceptable salts thereof, as being useful as an inhibitor of BRafactivity, particularly in the treatment of cancer, in PCT patentpublication WO2009/137391. Dabrafenib is embodied by Examples 58athrough 58e of the application.

Dabrafenib is a potent and selective RAF kinase inhibitor of human wildtype BRAF and CRAF enzymes as well as the mutant forms BRAFV600E,BRAFV600K and BRAFV600D. Accordingly, one embodiment of the inventionincludes adjuvant treatment of patients having BRAFV600E, BRAFV600K,and/or BRAFV600D mutation-positive melanoma which has been resected.

The term “trametinib” as used herein means the MEK inhibitor representedby the structure of formula (I):

or a pharmaceutically acceptable salt or solvate thereof. Trametinib ispreferably administered as a solvate in the form ofN-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamidedimethyl sulfoxide (solvate). Depending on naming convention, thecompound of formula (I) may also properly be referred to asN-{3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}acetamide.

Trametinib is disclosed and claimed, along with pharmaceuticallyacceptable salts thereof, and also as solvates thereof, as being usefulas an inhibitor of MEK activity, particularly in treatment of cancer, inWO 2005/121142. Trametinib can be prepared as described in WO2005/121142.

Suitably, trametinib is in the form of a dimethyl sulfoxide solvate.Suitably, trametinib is in the form of a sodium salt. Suitably,trametinib is in the form of a solvate selected from: hydrate, aceticacid, ethanol, nitromethane, chlorobenzene, 1-pentancol, isopropylalcohol, ethylene glycol and 3-methyl-1-butanol. These solvates and saltforms can be prepared by one of skill in the art from the description inWO 2005/121142.

As used herein, “resection” is understood to mean surgical removal ofmalignant tissue characteristic of melanoma from a human patient.According to one embodiment, resection shall be understood to meanremoval of malignant tissue such that the presence of remainingmalignant tissue within said patient is undetectable with availablemethods. According to another embodiment of the invention, resectionshall be understood to mean removal of melanoma such that the presenceof remaining melanoma with said patient is undetectable.

As used herein, “treatment” or “adjuvant treatment” is understood torefer to the administration of a drug or drugs to a patient aftersurgical resection of one or more cancerous tumors, where all detectableand resectable disease (e.g. cancer) has been removed from the patient,but where there remains a statistical risk of relapse due to occultdisease, for the purpose of diminishing the likelihood or the severityof reoccurrence or the disease, or to delay the onset of the biologicalmanifestation of the reoccurrence of the disease.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

While it is possible that, for use in therapy, dabrafenib and trametinibmay be administered as the raw chemical, it is possible to present theactive ingredient as a pharmaceutical composition. Accordingly, theinvention further provides pharmaceutical compositions, which includedabrafenib and/or trametinib, and one or more pharmaceuticallyacceptable carriers, diluents, or excipients. The carrier(s), diluent(s)or excipient(s) must be acceptable in the sense of being compatible withthe other ingredients of the formulation, capable of pharmaceuticalformulation, and not deleterious to the recipient thereof. In accordancewith another aspect of the invention there is also provided a processfor the preparation of a pharmaceutical composition including admixingdabrafenib and/or trametinib, with one or more pharmaceuticallyacceptable carriers, diluents or excipients. Such elements of thepharmaceutical compositions utilized may be presented in separatepharmaceutical combinations or formulated together in one pharmaceuticalcomposition. Accordingly, the invention further provides a combinationof pharmaceutical compositions one of which includes trametinib and oneor more pharmaceutically acceptable carriers, diluents, or excipientsand a pharmaceutical composition containing dabrafenib and one or morepharmaceutically acceptable carriers, diluents, or excipients.

Dabrafenib and/or trametinib may be administered by any appropriateroute. Suitable routes include oral, rectal, nasal, topical (includingbuccal and sublingual), vaginal, and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal, and epidural). Itwill be appreciated that the preferred route may vary with, for example,the condition of the recipient of the combination and the cancer to betreated. It will also be appreciated that each of the agentsadministered may be administered by the same or different routes andthat the compounds may be compounded together in a pharmaceuticalcomposition.

Dabrafenib and trametinib may be employed in combination in accordancewith the invention by administration simultaneously in a unitarypharmaceutical composition including both compounds. Alternatively, thecombination may be administered separately in separate pharmaceuticalcompositions, each including one of the dabrafenib and trametinib in asequential manner wherein, for example, trametinib or dabrafenib isadministered first and the other second. Such sequential administrationmay be close in time (eg. simultaneously) or remote in time.Furthermore, it does not matter if the compounds are administered in thesame dosage form, e.g. one compound may be administered topically andthe other compound may be administered orally. Suitably, both compoundsare administered orally. Thus in one embodiment, one or more doses oftrametinib are administered simultaneously or separately with one ormore doses of dabrafenib.

Suitably, the amount of trametinib (based on weight ofunsalted/unsolvated amount) administered as part of the combinationaccording to the present invention will be an amount selected from about0.125 mg to about 10 mg; suitably, the amount will be selected fromabout 0.25 mg to about 9 mg; suitably, the amount will be selected fromabout 0.25 mg to about 8 mg; suitably, the amount will be selected fromabout 0.5 mg to about 8 mg; suitably, the amount will be selected fromabout 0.5 mg to about 7 mg; suitably, the amount will be selected fromabout 1 mg to about 7 mg; suitably, the amount will be about 5 mg.Accordingly, the amount of trametinib administered as part of thecombination according to the present invention will be an amountselected from about 0.125 mg to about 10 mg. For example, the amount oftrametinib administered as part of the combination according to thepresent invention can be 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg.

Suitably, the amount of dabrafenib (based on weight ofunsalted/unsolvated amount) administered as part of the combinationaccording to the present invention will be an amount selected from about10 mg to about 600 mg. Suitably, the amount will be selected from about30 mg to about 300 mg; suitably, the amount will be selected from about30 mg to about 280 mg; suitably, the amount will be selected from about40 mg to about 260 mg; suitably, the amount will be selected from about60 mg to about 240 mg; suitably, the amount will be selected from about80 mg to about 220 mg; suitably, the amount will be selected from about90 mg to about 210 mg; suitably, the amount will be selected from about100 mg to about 200 mg, suitably, the amount will be selected from about110 mg to about 190 mg, suitably, the amount will be selected from about120 mg to about 180 mg, suitably, the amount will be selected from about130 mg to about 170 mg, suitably, the amount will be selected from about140 mg to about 160 mg, suitably, the amount will be 150 mg.Accordingly, the amount of dabrafenib administered as part of thecombination according to the present invention will be an amountselected from about 10 mg to about 300 mg. For example, the amount ofdabrafenib administered as part of the combination according to thepresent invention is suitably selected from 10 mg, 20 mg, 30 mg, 40 mg,50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg,115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg,160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg,205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg,250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg,295 mg and 300 mg. Suitably, the selected amount of dabrafenib isadministered from 1 to 4 times a day. Suitably, the selected amount ofdabrafenib is administered twice a day. Suitably, dabrafenib isadministered at an amount of 150 mg twice a day. Suitably, the selectedamount of dabrafenib is administered once a day.

In another embodiment, the combination of the invention may be employedwith other therapeutic methods of cancer treatment. In particular, inanti-neoplastic therapy, combination therapy with otherchemotherapeutic, hormonal, antibody agents as well as surgical and/orradiation treatments other than those mentioned above are envisaged.Combination therapies according to the present invention thus includethe administration of trametinib and dabrafenib as well as optional useof other therapeutic agents including other anti-neoplastic agents. Suchcombination of agents may be administered together or separately and,when administered separately this may occur simultaneously orsequentially in any order, both close and remote in time. In oneembodiment, the pharmaceutical combination includes trametinib anddabrafenib, and optionally at least one additional anti-neoplasticagent.

BACKGROUND

Cutaneous melanoma is the most aggressive form of all skin cancers.Although it represents only 4% of all cancers, its incidence iscontinuing to rise in the world at a rate exceeding all other cancers[Jemal, 2007]. Worldwide it is expected that approximately 132,000people will be diagnosed with melanoma each year and approximately37,000 people are expected to die of the disease annually [WHO, 2012].

Surgical resection is the treatment of choice for localized melanoma andfrequently results in cures for early stage (I and II) disease, with a90% long term (10-year) survival rate for stage I disease [Balch, 2009].However, patients with lymph node involvement ≥1 mm, including thosedetected only by sentinel lymph node biopsy, are at high risk of bothlocal and distant relapse after definitive surgery due to the frequentpresence of distant micrometastatic disease at presentation [Kirkwood,2001; Van Akkooi, 2009]. Approximately half of these patients willultimately die of metastatic disease [Markovic, 2007], and the morbidityfrom uncontrolled relapses is also considerable. Thus there is a needfor effective adjuvant therapy for high-risk patients to prevent diseaserelapse after surgical resection of the primary tumor.

Although significant progress has been made recently with new treatmentsfor metastatic melanoma, therapeutic options in the adjuvant settingremain limited. Many agents have been evaluated as potential therapiesfor the adjuvant treatment of melanoma however almost all havedemonstrated little or no benefit [Schuchter, 2004]. The NationalComprehensive Cancer Network (NCCN) treatment guidelines for melanomarecommend clinical trials, observation and interferon as the threetherapy options for the adjuvant treatment of melanoma with clinicaltrials as the preference [NCCN, 2012]. Although high-dose interferon iscurrently the only approved therapy for the adjuvant treatment ofmelanoma it is not widely accepted as the standard of care. Increasingevidence surrounding a questionable survival benefit, a high incidenceof serious toxicities, and negligible benefit for patients with bulkierdisease makes it an unattractive therapy for most patients andclinicians [Schuchter, 2004]. Thus there is a need for more effectivetherapies with an acceptable safety profile in the adjuvant setting.

Study Design

This is a two-arm, randomized, double-blind Phase III study ofdabrafenib in combination with trametinib versus two placebos in theadjuvant treatment of melanoma after surgical resection. Patients withcompletely resected, histologically confirmed, BRAF V600E/Kmutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm),IIIb or IIIc] cutaneous melanoma will be screened for eligibility.Approximately 852 subjects will be randomized in a 1:1 ratio to receiveeither dabrafenib (150 mg BID) and trametinib (2 mg once daily)combination therapy or two placebos for each for 12 months.

Doses of study treatment may be modified and/or interrupted formanagement of toxicities associated with study treatment.

The benefit of the dabrafenib/trametinib combination compared toplacebos will be evaluated through the primary endpoint ofinvestigator-assessed relapse free survival (RFS). Crossover is notpermitted.

Subjects in both arms will receive treatment for 12 months or untildisease recurrence, death, unacceptable toxicity, or withdrawal ofconsent. Subjects will be followed for disease recurrence and survivalduring and after the treatment period.

The primary objective for this study is to evaluate the efficacy ofdabrafenib and trametinib combination therapy compared to two placeboswith respect to relapse-free survival (RFS) in patients with completelyresected, histologically confirmed, BRAF V600E/K high-risk, stage IIIcutaneous melanoma. Secondary efficacy objectives include:

-   -   To evaluate the overall survival (OS) of dabrafenib and        trametinib combination therapy compared to placebo    -   To assess distant metastasis-free survival (DMFS)    -   To assess freedom from relapse (FFR)

Discussion of Design

The ultimate goal of adjuvant therapy is to improve the cure rate aftersurgery through eradication of occult micrometastatic disease. Notablesuccesses have been achieved in oncology when highly effective therapieswere available for advanced stage disease (e.g., breast cancer,Hodgkin's and non-Hodgkin's lymphoma, embryonal tumors, osteosarcoma).High-risk, resected BRAF V600E/K mutation positive melanoma representsanother attractive setting for testing this paradigm since: 1) thepopulation is at high risk for relapse and death without furthertherapy; 2) the BRAF/MEK combination is both highly effective and can betargeted to the population most likely to benefit, and 3) thecombination of dabrafenib and trametinib should be at least as welltolerated as cytotoxic chemotherapy or high-dose interferon and thushave acceptable risk:benefit if the study objectives are met.

This study is designed to compare dabrafenib and trametinib incombination versus two placebos with regard to RFS, which is a directmeasurement of anti-tumor effect. RFS was selected as the primaryendpoint based upon historical precedent (peginterferon alfa-2b,Sylatron) and because it will not be subject to confounding fromsubsequent therapy, as would OS. Since relapses are accompanied byconsiderable disease- and treatment-related morbidity, RFS is a truemeasure of patient benefit.

Subject Selection and Discontinuation/Completion Criteria

Approximately 852 subjects will be randomized, 1:1 to combinationtherapy (n=426) and to placebos (n=426).

Inclusion Criteria

Subjects eligible for enrolment in the study must meet all of thefollowing criteria:

-   -   1. Is years of age.    -   2. Has signed written informed consent.    -   3. Completely resected histologically confirmed high-risk [Stage        IIIa (LN metastasis >1 mm), IIIb or IIIc] cutaneous melanoma        determined to be V600E/K mutation positive using the bioMerieux        (bMX) investigational use only (ILK)) THxID BRAF Assay (IDE:        G120011). The testing will be conducted by a central reference        laboratory. Patients presenting with initial resectable lymph        node recurrence after a diagnosis of Stage I or II melanoma are        eligible.    -   4. Must be surgically rendered free of disease no more than 12        weeks before randomization.    -   5. Recovered from definitive surgery (e.g. no uncontrolled wound        infections or indwelling drains).    -   6. Able to swallow and retain oral medication and must not have        any clinically significant gastrointestinal abnormalities that        may alter absorption such as malabsorption syndrome or major        resection of the stomach or bowels.    -   7. Eastern Cooperative Oncology Group (ECOG) Performance Status        of 0-1.    -   8. Must have adequate organ function as defined in Table 1:

TABLE 1 Definitions for Adequate Baseline Organ Function SystemLaboratory Values Hematologic ANC ≥1.2 × 10⁹/L Hemoglobin ≥9 g/dLPlatelet count ≥100 × 10⁹/L PT/INR^(a) and PTT ≤1.5 × ULN HepaticAlbumin ≥2.5 g/dL Total bilirubin ≤1.5 × ULN AST and ALT ≤2.5 × ULNRenal Serum creatinine^(b) ≤1.5 mg/dL Cardiac Left Ventricular Ejectionfraction ≥LLN by ECHO (LVEF)^(c) Abbreviations: ALT = alaninetransaminase; ANC = absolute neutrophil count; AST = aspartateaminotransferase; INR = international normalized ratio; LLN = lowerlimit of normal; PT = prothrombin time; PTT = partial thromboplastintime; ULN = upper limit of normal. ^(a)Subjects receivinganticoagulation treatment may be allowed to participate with INRestablished within the therapeutic range prior to randomization. ^(b)Ifserum creatinine is > 1.5 mg/dL, calculate creatinine clearance usingstandard Cockcroft-Gault formula. Creatinine clearance must be ≥ 50mL/min to be eligible. ^(c)ECHO scans must be used throughout the study

-   -   9. Women of childbearing potential must have a negative serum        pregnancy test within 7 days of first dose of study treatment        and agree to use effective contraception, from 14 days prior to        randomization, throughout the treatment period and for 4 months        after the last dose of study treatment.    -   10. French subjects: In France, a subject will be eligible for        inclusion in this study only if either affiliated to or a        beneficiary of a social security category.

Exclusion Criteria

Subjects meeting any of the following criteria must not be enrolled inthe study:

-   -   1. Known mucosal or ocular melanoma or the presence of        unresectable in-transit metastases.    -   2. Evidence of distant metastatic disease on screening        evaluation.    -   3. Prior systemic anti-cancer treatment (chemotherapy,        immunotherapy, biologic therapy, vaccine therapy, or        investigational treatment) and radiotherapy for melanoma. Prior        surgery for melanoma is allowed.    -   4. Taken an investigational drug within 28 days or 5 half-lives,        whichever is longer, prior to randomization.    -   5. Current or expected use of a prohibited medication.    -   6. Known immediate or delayed hypersensitivity reaction or        idiosyncrasy to drugs chemically related to the study        treatments, their excipients, and/or dimethyl sulfoxide (DMSO).    -   7. Known Human Immunodeficiency Virus (HIV).    -   8. A history of known glucose-6-phosphate dehydrogenase (G6PD)        deficiency.    -   9. History of another malignancy including melanoma or a        concurrent malignancy except as noted below:        -   Exceptions: Subjects who have been disease-free for 5 years,            or subjects with a history of completely resected            non-melanoma skin cancer or successfully treated in situ            carcinoma are eligible, for example cervical cancer in situ,            atypical melanocytic hyperplasia or melanoma in situ,            multiple primary melanomas, or other malignancies for which            the patient has been disease free for >5 years.    -   10. A history or evidence of cardiovascular risk including any        of the following:        -   a. A QT interval corrected for heart rate using the Bazett's            formula (QTcB) ≥480 msec;        -   b. A history or evidence of current clinically significant            uncontrolled arrhythmias;        -   c. A history of acute coronary syndromes (including            myocardial infarction or unstable angina), coronary            angioplasty, or stenting within 6 months prior to            randomization        -   d. A history or evidence of current Class II congestive            heart failure as defined by the New York Heart Association            (NYHA) guidelines        -   e. Patients with intra-cardiac defibrillators or permanent            pacemakers.        -   f. Abnormal cardiac valve morphology (≥grade 2) documented            by echocardiogram (subjects with grade 1 abnormalities            [i.e., mild regurgitation/stenosis] can be entered on            study). Subjects with moderate valvular thickening should            not be entered on study.        -   g. Treatment refractory hypertension defined as a blood            pressure of systolic>140 mm Hg and/or diastolic >90 mm Hg            which cannot be controlled by anti-hypertensive therapy    -   11. A history or current evidence/risk of retinal vein occlusion        (RVO) or central serous retinopathy (CSR) including:        -   a. Presence of predisposing factors to RVO or CSR (e.g.,            uncontrolled glaucoma or ocular hypertension, uncontrolled            hypertension, uncontrolled diabetes mellitus, or a history            of hyperviscosity or hypercoagulability syndromes); or        -   b. Visible retinal pathology as assessed by ophthalmic            examination that is considered a risk factor for RVO or CSR            such as:            -   i. Evidence of new optic disc cupping;            -   ii. Evidence of new visual field defects on automated                perimetry;            -   iii. Intraocular pressure >21 mm Hg as measured by                tonography.    -   12. Interstitial lung disease or pneumonitis.    -   13. Any serious or unstable pre-existing medical conditions        (aside from malignancy exceptions specified above), psychiatric        disorders, or other conditions that, in the opinion of the        investigator, could interfere with the subject's safety,        obtaining informed consent, or compliance with study procedures.    -   14. Pregnant or nursing females.

Permanent Discontinuation from Study Treatment and Subject CompletionCriteria

Subjects will receive study treatments for twelve months or untildisease recurrence. During the protocol defined treatment period studytreatment(s) may be permanently discontinued for the following reasons:

-   -   death    -   unacceptable adverse event, including meeting stopping criteria        for liver chemistry and/or for hematologic and other        non-hematologic toxicity.    -   deviation(s) from the protocol    -   request of the subject or proxy    -   investigator's discretion    -   subject is lost to follow-up    -   study is closed or terminated.

If disease recurs prior to the completion of the 12 month treatmentperiod, study treatment should be discontinued and follow-up assessmentsshould be conducted. All subjects who permanently discontinue studytreatment without evidence of disease recurrence will also be followedfor disease recurrence according to the protocol schedule until:

-   -   Withdrawal of consent    -   Death, or    -   Study completion

Follow-up will continue for all subjects including those with diseaserecurrence, until the study is considered to be complete after which allprotocol-required assessments and procedures will be discontinued.

A subject will be considered to have completed the study if the subjectdies during the study treatment or follow-up period. A subject will beconsidered to have withdrawn from the study if the subject has not diedand is lost to follow-up, has withdrawn consent, at the investigator'sdiscretion is no longer being followed or if the study isclosed/terminated. Subjects who are ongoing at the time the study isclosed/terminated will be considered to have completed the study.

Study Assessments

Subjects will be assessed with computed tomography (CT) or magneticresonance imaging (MRI) at Screening and during treatment and thepost-treatment follow-up period. Clinical assessments including vitalsigns and physical examinations, 12-lead ECG, ECHO, eye exams, chemistryand hematology laboratory values, and AEs will be monitored andevaluated. Subjects will also be followed for survival.

Study Treatment

Subjects will be identified by a unique subject number that will remainconsistent for the duration of the study.

Upon completion of all the required screening assessments, eligiblesubjects will be registered into the GSK interactive voice responsesystem (IVRS), by the investigator or authorized site staff.

Randomization will be done centrally using a randomization schedulegenerated by the GSK Biostatistical Department, which will assignsubjects in a 1:1 ratio to:

-   -   dabrafenib and trametinib combination therapy;    -   dabrafenib and trametinib placebos

Blinding

Study treatment will be double-blinded.

Dose Modification Guidelines

The severity of adverse events will be graded utilizing the NationalCancer Institute (NCI) CTCAE, version 4.0. Supportive and dosemodification guidelines will be provided to investigators in event ofadverse or serious adverse event(s), including drug termination andre-starting criteria. Drug-drug interaction and overdose informationwill also be provided to the investigators.

Endpoints

The primary efficacy endpoint of this study is relapse free survival(RFS) which is defined as the time from randomization to diseaserecurrence or death from any cause. Recurrence of or death from the samecancer and all deaths from other causes are events. Treatment emergentmalignancies (excluding second melanomas) will not be considered asevents, and loss to follow-up is censored.

The secondary efficacy endpoints of this study are:

-   -   Overall Survival (OS) defined as the interval from randomization        to the date of death, irrespective of the cause of death;        patients still alive will be censored at the date of the last        contact.    -   Distant metastasis-free survival (DMFS), defined as the interval        from randomization to the date of first distant metastasis or        date of death, whichever occurs first. Patients alive and        without distant metastasis are censored at the date of last        assessment.    -   Freedom from relapse (FFR), defined as interval from        randomization to local or distant recurrence or new melanoma        primary, with censoring of patients dying from causes other than        melanoma or treatment-related toxicity at the date of death.        Incidence of new melanoma will not be considered as an event.        Patients alive without recurrence or with second primary cancers        will be censored at the date of last assessment.

What is claimed:
 1. A method of providing adjuvant treatment to apatient with a prior diagnosis of melanoma which has been resected,comprising the step of administering to such a patient therapeuticallyeffective doses of dabrafenib and trametinib for a time periodsufficient to increase relapse-free survival (RFS).
 2. The method ofclaim 1, wherein dabrafenib is administered at an amount of 150 mg twicea day.
 3. The method of claim 1, wherein trametinib is administered atan amount of 2 mg once daily.
 4. The method of claim 1, wherein thepatient has a prior diagnosis of stage III melanoma which been resected.5. The method of claim 1, wherein the patient has a prior diagnosis ofBRAF V600 mutation-positive melanoma which has been resected.
 6. Amethod of increasing relapse-free survival (RFS) of a patient afterresection of melanoma, comprising the administration of a) dabrafeniband b) trametinib.
 7. The method of claim 6, wherein the melanoma isBRAF V600 mutation-positive.
 8. A composition comprising the combinationof dabrafenib and trametinib for use in increasing relapse-free survival(RFS) in a patient after resection of melanoma.